Epigenetic dynamics during sexual reproduction: At the nexus of developmental control and genomic integrity.

Epigenetic marks influence gene regulation and genomic stability via the repression of transposable elements. During sexual reproduction, tight regulation of the epigenome must take place to maintain the repression of transposable elements while still allowing changes in cell-specific transcriptional programs. In plants, epigenetic marks are reorganized during reproduction and a reinforcing mechanism takes place to ensure transposable elements silencing. In this review, we describe the latest advances in characterizing the cell-specific epigenetic changes occurring from sporogenesis to seed development, with a focus on DNA methylation. We highlight the epigenetic co-regulation between transposable elements and developmental genes at different stages of plant reproduction

DNA METHYLTRANSFERASE 3 (MET3) is regulated by Polycomb Group complex during Arabidopsis endosperm development

Complex epigenetic changes occur during plant reproduction. These regulations ensure the proper transmission of epigenetic information as well as allowing for zygotic totipotency. In Arabidopsis, the main DNA methyltransferase is called MET1 and is responsible for methylating cytosine in the CG context. The Arabidopsis genome encodes for three additional reproduction-specific homologs of MET1, namely MET2a, MET2b and MET3. In this paper, we show that the DNA methyltransferase MET3 is expressed in the seed endosperm and its expression is further restricted to the chalazal endosperm. MET3 is biallelically expressed in the endosperm but displays a paternal expression bias. We found that MET3 expression is regulated by the Polycomb complex proteins FIE and MSI1. Seed development is not impaired in met3 mutant, and we could not observe significant transcriptional changes in met3 mutant. Interestingly, we found that MET3 regulates gene expression in a Polycomb mutant background suggesting a further complexification of the interplay between H3K27me3 and DNA methylation in the seed endosperm

DNA Methyltransferase 3 (MET3) is regulated by Polycomb group complex during Arabidopsis endosperm development

Complex epigenetic changes occur during plant reproduction. These regulations ensure the proper transmission of epigenetic information as well as allowing for zygotic totipotency. In Arabidopsis, the main DNA methyltransferase is called MET1 and is responsible for methylating cytosine in the CG context. The Arabidopsis genome encodes for three additional reproduction-specific homologs of MET1, namely MET2a, MET2b and MET3. In this paper, we show that the DNA methyltransferase MET3 is expressed in the seed endosperm and its expression is later restricted to the chalazal endosperm. MET3 is biallelically expressed in the endosperm but displays a paternal expression bias. We found that MET3 expression is regulated by the Polycomb complex proteins FIE and MSI1. Seed development is not impaired in met3 mutant, and we could not observe significant transcriptional changes in met3 mutant. MET3 might regulates gene expression in a Polycomb mutant background suggesting a further complexification of the interplay between H3K27me3 and DNA methylation in the seed endosperm

Methylome Response to Proteasome Inhibition by Pseudomonas syringae Virulence Factor Syringolin A

DNA methylation is an important epigenetic mark required for proper gene expression and silencing of transposable elements. DNA methylation patterns can be modified by environmental factors such as pathogen infection, in which modification of DNA methylation can be associated with plant resistance. To counter the plant defense pathways, pathogens produce effector molecules, several of which act as proteasome inhibitors. Here, we investigated the effect of proteasome inhibition by the bacterial virulence factor syringolin A (SylA) on genome-wide DNA methylation. We show that SylA treatment results in an increase of DNA methylation at centromeric and pericentromeric regions of Arabidopsis chromosomes. We identify several CHH differentially methylated regions (DMRs) that are enriched in the proximity of transcriptional start sites. SylA treatment does not result in significant changes in small RNA composition. However, significant changes in genome transcriptional activity can be observed, including a strong upregulation of resistance genes that are located on chromosomal arms. We hypothesize that DNA methylation changes could be linked to the upregulation of some atypical members of the de novo DNA methylation pathway, namely AGO3, AGO9, and DRM1. Our data suggests that modification of genome-wide DNA methylation resulting from an inhibition of the proteasome by bacterial effectors could be part of an epi-genomic arms race against pathogens. [Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Evolution of CG Methylation Maintenance Machinery in Plants

Cytosine methylation is an epigenetic mark present in most eukaryotic genomes that contributes to the regulation of gene expression and the maintenance of genome stability. DNA methylation mostly occurs at CG sequences, where it is initially deposited by de novo DNA methyltransferases and propagated by maintenance DNA methyltransferases (DNMT) during DNA replication. In this review, we first summarize the mechanisms maintaining CG methylation in mammals that involve the DNA Methyltransferase 1 (DNMT1) enzyme and its cofactor, UHRF1 (Ubiquitin-like with PHD and RING Finger domain 1). We then discuss the evolutionary conservation and diversification of these two core factors in the plant kingdom and speculate on potential functions of novel homologues typically observed in land plants but not in mammals

Methylome dynamic upon proteasome inhibition by the Pseudomonas syringae virulence factor Syringolin A

DNA methylation is an important epigenetic mark required for proper gene expression and silencing of transposable elements. DNA methylation patterns can be modified by environmental factors such as pathogen infection, where modification of DNA methylation can be associated with plant resistance. To counter the plant defense pathways, pathogens produce effectors molecule, several of which act as proteasome inhibitors. Here we investigated the effect of proteasome inhibition by the bacterial virulence factor Syringolin A on genome-wide DNA methylation. We show that Syringolin A treatment results in an increase of DNA methylation at centromeric and pericentromeric regions of Arabidopsis chromosomes. We identify several CHH DMRs that are enriched in the proximity of transcriptional start sites. Syringolin A treatment does not result in significant changes in small RNA composition. However, significant changes in genome transcriptional activity can be observed, including a strong upregulation of resistance genes that are located on chromosomal arms. We hypothesize that DNA methylation changes could be linked to the upregulation of some atypical members of the de novo DNA methylation pathway: AGO3, AGO9 and DRM1. Our data suggests that modification of genome-wide DNA methylation resulting from an inhibition of the proteasome by bacterial effectors could be part of a epi-genomic arms race against pathogens.Competing Interest StatementThe authors have declared no competing interest

Methylome response to proteasome inhibition by the Pseudomonas syringae virulence factor Syringolin A.

DNA methylation is an important epigenetic mark required for proper gene expression and silencing of transposable elements. DNA methylation patterns can be modified by environmental factors such as pathogen infection, where modification of DNA methylation can be associated with plant resistance. To counter the plant defense pathways, pathogens produce effector molecules, several of which act as proteasome inhibitors. Here we investigated the effect of proteasome inhibition by the bacterial virulence factor Syringolin A on genome-wide DNA methylation. We show that Syringolin A treatment results in an increase of DNA methylation at centromeric and pericentromeric regions of Arabidopsis chromosomes. We identify several CHH DMRs that are enriched in the proximity of transcriptional start sites. Syringolin A treatment does not result in significant changes in small RNA composition. However, significant changes in genome transcriptional activity can be observed, including a strong upregulation of resistance genes that are located on chromosomal arms. We hypothesize that DNA methylation changes could be linked to the upregulation of some atypical members of the de novo DNA methylation pathway: AGO3, AGO9 and DRM1. Our data suggests that modification of genome-wide DNA methylation resulting from an inhibition of the proteasome by bacterial effectors could be part of an epi-genomic arms race against pathogens

Resilience after severe critical illness: a prospective, multicentre, observational study (RESIREA)

International audienceAbstract Background Critical-illness survivors may experience post-traumatic stress disorder (PTSD) and quality-of-life impairments. Resilience may protect against psychological trauma but has not been adequately studied after critical illness. We assessed resilience and its associations with PTSD and quality of life, and also identified factors associated with greater resilience. Methods This prospective, multicentre, study in patients recruited at 41 French ICUs was done in parallel with the NUTRIREA-3 trial in patients given mechanical ventilation and vasoactive amines for shock. Three months to one year after intensive-care-unit admission, survivors completed the Connor-Davidson Resilience Scale (CD-RISC-25), Impact of Event-Revised scale for PTSD symptoms (IES-R), SF-36 quality-of-life scale, Multidimensional Scale of Perceived Social Support (MSPSS), and Brief Illness Perception Questionnaire (B-IPQ). Results Of the 382 included patients, 203 (53.1%) had normal or high resilience (CD-RISC-25 ≥ 68). Of these resilient patients, 26 (12.8%) had moderate to severe PTSD symptoms (IES-R ≥ 24) vs. 45 (25.4%) patients with low resilience ( p = 0.002). Resilient patients had higher SF-36 scores. Factors independently associated with higher CD-RISC-25 scores were higher MSPSS score indicating stronger social support (OR, 1.027; 95%CI 1.008–1.047; p = 0.005) and lower B-IPQ scores indicating a more threatening perception of the illness (OR, 0.973; 95%CI 0.950–0.996; p = 0.02). Conclusions Resilient patients had a lower prevalence of PTSD symptoms and higher quality of life scores, compared to patients with low resilience. Higher scores for social support and illness perception were independently associated with greater resilience. Thus, our findings suggest that interventions to strengthen social support and improve illness perception may help to improve resilience. Such interventions should be evaluated in trials with PTSD mitigation and quality-of-life improvement as the target outcomes